The role of mechanical force in the regulation of fibroblast function: Implications for enhanced collagen deposition during pulmonary vascular remodelling

Enhanced collagen deposition is a feature of pulmonary vascular remodelling associated with pulmonary hypertension. Furthermore, its deposition is thought to be a key event in the progressive sequence of changes that lead to hypertrophied vessels which are not amenable to current forms of therapy. For that reason there is great interest in the mechanisms regulating collagen deposition, with the belief that such an understanding would make us better able to design therapeutic agents to prevent or reverse this process. The major collagen-producing cell in the vessel wall is the adventitial fibroblast. We hypothesize that the enhanced transmural pressure imposed as a result of the hypertension, leads to increased mechanical strain on fibroblasts resulting in increased fibroblast replication as well as a stimulation of fibroblast collagen synthesis. The mechanisms involved in strain-induced fibroblast stimulation are unknown, however we present evidence here that an important initial response is the release of autocrine growth factors such as platelet-derived growth factor which not only acts as a fibroblast mitogen but also stimulates fibroblast migration and collagen production. Current techniques are allowing us to identify, more precisely, the mediators involved and their transduction mechanisms.